Alterations In Intestinal Microbiome And Intestinal Barrier In Patients With Obstructive Sleep Apnea

BackgroundObstructive sleep apnea（OSA）is associated with repeated upper airway collapse,intermittent hypoxia,and intestinal barrier dysfunction,often accompanied by multiple system and multiple organ damage.Hypoxia is the root cause,but the exact mechanism is still unclear.Recent studies have discovered that changes of intestinal microbiota exist in animal models of OSA.The imbalance of intestinal microbiota increases OSA-induced hypertension,hyperlipidemia,coronary heart disease and other multi-system and multi-organ related complications.Therefore,it is believed that there may also be imbalanced intestinal microbiota in patients with OSA,and impaired intestinal barrier may affect or be affected by the intestinal microbiome.ObjectivesTo clinically evaluate whether the composition and structure of the intestinal microbiota in patients with OSA are related to OSA and the impaired intestinal barrier,and explore whether continuous positive airway pressure（CPAP）therapy can reverse the above changes.It provides a new idea for whether targeted therapy of intestinal microorganism should be added to CPAP treatment in the future.MethodsA prospective cohort was used,including patients who were admitted to our department due to snoring,lethargy and other symptoms and met the selection criteria.Sleep apnea was diagnosed by overnight polysomnography and baseline data were collected.Fecal samples and blood samples were obtained from subjects to measure gut microbiome composition（based on 16S rDNA gene amplicon sequencing）and intestinal barrier biomarkers—intestinal fatty acid binding protein（I-FABP）(（based on ELISA）combined with D-lactic acid（D-LA）（based on colorimetry assay）.After treatment with CPAP,blood and stool samples were collected and analyzed again to further verify their correlation.Results1.Plasma D-LA and I-FABP levels were significantly higher in patients with OSA.Increased glucose,triglycerides,leukocytes,neutrophils,and monocytes were also noted in OSA patients.It was also observed that the increase in D-LA and I-FABP exhibited the strongest positive association with AHI（r=0.443,P<0.001;r=0.645,P<0.001,respectively）.Multivariate regression analysis showed that D-LA（B=0.823,P<0.001）and I-FABP（B=0.002,P=0.017）were independently associated with OSA.2.The severity of OSA was related to differences intestinal microbiome in βdiversity.The intestinal microbiome of severe OSA were enriched with Fusobacterium,Megamonasa,Lachnospiraceae_UCG₀06,and decreased with Anaerostipes compared to no OSA subjects.The intestinal microbiota of patients with high intestinal barrier biomarkers were enriched with Ruminococcus₂,Lachnoclostridium,Lachnospiraceae_UCG₀06,Alloprevotella,and decreased with Senegalimascilia.Multivariate regression analysis found that Fusobacterium and Peptoclostridium in the severe OSA group were independent risk factors for OSA.The dominant genera of severe OSA were not only related to D-LA and I-FABP,but also related to blood glucose,blood lipid,neutrophils and monocyte counts.Network analysis identified association between intestinal microbiome,intestinal barrier biomarkers and AHI.3.The plasma D-LA（P=0.024）and I-FABP（P=0.039）levels decreased significantly in patients who were treated with CPAP.The α or β diversity of intestinal microbiome did not change significantly,but the abundance of the microbiome increased significantly.The largest increase in relative abundance at the phylum level was Firmicutes,at the genus level was Bacteroides,and Anaerostipes had also increased.ConclusionWe proved that dysregulation of intestinal microbiome and impaired barrier are not only associated with OSA,but also with metabolism and inflammation.We also demonstrated that altered OSA microbiome is associated with impaired intestinal barrier.CPAP treatment may improve the intestinal damage and reverse part of the intestinal microbiome imbalance.These changes may play a pathophysiological role in OSA associated systemic inflammation and metabolic syndrome.